The long term objective of this project is to establish the molecular mechanisms of analgesia, tolerance and dependence on narcotic drugs. These studies will be carried out in simple systems in which specific narcotic effects could be demonstrated. We will study the inhibition of acetylcholine release produced by narcotics and the interactions of calcium and narcotics at the level of the neuronal membrane. These studies will give important clues regarding the primary biochemical lesion produced by opioids and will provide the theoretical and experimental models for finding a final solution to the medical and social problems caused by physical dependence and drug-seeking behavior. Human subjects are not involved in this project.